Piperidine derivatives useful as ccr5 antagonists

ABSTRACT

The present invention provides a compound of the formula  
                 
or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as defined in the specification. The present invention also provides pharmaceutical compositions containing the compound of this invention, and methods of treatment using the compound of this invention. The invention also relates to the use of a combination of a compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.

PRIORITY APPLICATION

This application is a divisional of U.S. application Ser. No.10/738,907, filed Dec. 17, 2003, which claims the benefit of U.S.provisional Application Ser. No. 60/434,306, filed Dec. 18, 2002, bothof which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to piperidine derivatives useful asselective CCR5 antagonists, pharmaceutical compositions containing thecompound of this invention, and methods of treatment using the inventivecompounds. The invention also relates to the use of a combination of thecompound of this invention and one or more antiviral or other agentsuseful in the treatment of Human Immunodeficiency Virus (HIV). Theinvention further relates to the use of the compound of this invention,alone or in combination with another agent, in the treatment of solidorgan transplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis.

BACKGROUND OF INVENTION

The global health crisis caused by HIV, the causative agent of AcquiredImmunodeficiency Syndrome (AIDS), is unquestioned. While recent advancesin drug therapies have been successful in slowing the progression ofAIDS, there is still a need to find a safer, more efficient, lessexpensive way to control the virus.

It has been reported that the CCR5 gene plays a role in resistance toHIV infection. HIV infection begins by attachment of the virus to atarget cell membrane through interaction with the cellular receptor CD4and a secondary chemokine co-receptor molecule, and proceeds byreplication and dissemination of infected cells through the blood andother tissue. There are various chemokine receptors, but formacrophage-tropic HIV, believed to be the key pathogenic strain thatreplicates in vivo in the early stages of infection, the principalchemokine receptor required for the entry of HIV into the cell is CCR5.Therefore, interfering with the interaction between the viral receptorCCR5 and HIV can block HIV entry into the cell. The present inventionrelates to small molecules which are CCR5 antagonists.

CCR5 receptors have been reported to mediate cell transfer ininflammatory diseases such as arthritis, rheumatoid arthritis, atopicdermatitis, psoriasis, asthma and allergies. Inhibitors of suchreceptors are expected to be useful in the treatment of such diseases,and in the treatment of other inflammatory diseases or conditions suchas inflammatory bowel disease, multiple sclerosis, solid organtransplant rejection and graft v. host disease. WO 02/791194 disclosesother piperidine derivatives useful as CCR5 antagonists.

Other piperidine derivatives, which are muscarinic antagonists useful inthe treatment of cognitive disorders such as Alzheimer's disease, aredisclosed in U.S. Pat. Nos. 5,883,096, 6,037,352, 5,889,006, 5,952,349,and 5,977,138.

A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203(1998) disclose current clinical treatments of HIV-1 infections in manincluding at least triple drug combinations or so-called Highly ActiveAntiretroviral Therapy (“HAART”). HAART involves various combinations ofnucleoside reverse transcriptase inhibitors (“NNRTI”), non-nucleosidereverse transcriptase inhibitors (“NNRTI”) and HIV protease inhibitors(“PI”). In compliant drug-naive patients, HAART is effective in reducingmortality and the progression of HIV-1 to AIDS. However, these multidrugtherapies do not eliminate HIV-1 and long-term treatment usually resultsin multidrug resistance. Development of new drug therapies to providebetter HIV-1 treatment remains a priority.

SUMMARY OF THE INVENTION

The present invention provides a novel class of compounds as antagonistsof the CCR5 receptor, methods of preparing such compounds,pharmaceutical compositions containing one or more such compounds, andmethods of treatment, prevention or amelioration of one or more diseasesassociated with the CCR5 receptor.

One aspect of the invention relates to a compound having the generalstructure shown in Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

n is 0, 1, 2, 3 or 4;

s is 0, 1, 2, 3 or 4;

t is 1, 2, 3 or 4 with the provisos that

i) when n is 0 and s is 2, then t is 1, 3 or 4; and

ii) when n is 0 and t is 2, then s is 0, 1, 3 or 4;

X and Z can be the same or different with each being independently N orCH;

R¹ is H, alkyd, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²¹;

R², R⁴, R⁵, R⁶, and R⁷ can be the same or different each beingindependently H or alkyl;

R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;

or R² and R³ taken together are ═N(O-alkyl), ═N(OH), ═N—N(R²⁰R²¹) or═CH(alkyl) provided that when one or both of X and Z is N, R² and R³together are not ═CH(alkyl);

R⁸ is aryl, heteroaryl, fluorenyl; and diphenylmethyl, heteroaryl-N—

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is substituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R¹³, R¹⁴ and R¹⁵;

R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH, —OCH₃, —NH₂, —N(H)C(O)N(H)alkyl,—NHS(O₂)R²⁰ or —N(H)C(O)alkyl;

R¹¹ and R¹² can be the same or different and are each independentlyselected from the group consisting of alkyl, haloalkyl, halogen,—NR¹⁸R¹⁹, —OH, —CF₃, —OCH₃, —O-acyl and —OCF₃;

R¹³ is selected from the group consisting of H, R¹¹, aryl, —NO₂, —CN,—CH₂F, —CHF₂, —C(O)H, —CHO—NOR¹⁸, pyridyl-N-oxide, pyrimidinyl,pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰, —N(H)C(O)N(H)(haloalkyl),—N(H)C(O)N(H)(cycloalkylalkyl), —N(H)C(O)alkyl, —N(H)C(O)CF₃,—N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl, —N(S(O₂)CF₃)₂, —N(H)C(O)Oalkyl,cycloalkyl, —SR²¹, —S(O)R²¹, —S(O₂)R²¹, —S(O₂)N(H)(alkyl), —OS(O₂)alkyl,—OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹, —C(O)N(CH₂CH₂—O—CH₃)₂,—OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and —B(OC(CH₃)₂)₂;

R¹⁴ is selected from the group consisting of alkyl, haloalkyl, NH₂ andR¹⁵-phenyl;

R¹⁵ is 1 to 3 substituents selected from the group consisting of H,alkyl, haloalkyl, —CF₃, CO₂R¹⁹, —CN, alkoxy and halogen; wherein saidR¹⁵ moieties can be the same or different each being independentlyselected when there are more than one R¹⁵ present;

R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms;

R¹⁸, R¹⁹ and R²⁰ can each be the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, aryl and heteroaryl;

and

R²¹ is selected from the group consisting of alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl;

wherein each of said alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy,hydroxyalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkylin the definitions above can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, where said moieties are independently selected fromthe group consisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹,—C(O)NR¹⁸R¹⁹, —N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)OR¹⁸,—OCF₃, —CF₃, —S(O₂)R¹⁸ and —C(O)R¹⁸.

Another aspect of the invention relates to a pharmaceutical compositionfor treatment of HIV comprising one or more compounds of formula I.

Yet another aspect of the invention relates to a method of treatingHuman Immunodeficiency Virus (“HIV”) comprising administering to apatient in need of such treatment a therapeutically effective amount ofone or more compounds of formula I. A further aspect of the inventionrelates to a method of treating solid organ transplant rejection, graftv. host disease, arthritis, rheumatoid arthritis, inflammatory boweldisease, atopic dermatitis, psoriasis, asthma, allergies or multiplesclerosis comprising administering to a patient in need of suchtreatment a therapeutically effective amount of one or more compounds offormula I.

Still another aspect of this invention relates to a method of treatingHuman Immuno-deficiency Virus comprising administering to a patient inneed of such treatment the one or more compounds of formula I incombination with one or more antiviral or other agents useful in thetreatment.

A further aspect of this invention relates to a method of treating solidorgan transplant rejection, graft v. host disease, arthritis, rheumatoidarthritis inflammatory bowel disease, atopic dermatitis, psoriasis,asthma or allergies comprising administering to a patient in need ofsuch treatment one or more compounds of formula I in combination withone or more antiviral or other agents useful in the treatment.

The CCR5 antagonists and antiviral or other agents which are componentsof the combination can be administered in a single dosage oradministered separately A kit comprising separate dosage forms of theactives is also contemplated.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention discloses compounds representedby structural formula I,

or a pharmaceutically acceptable salt or solvate thereof; wherein thevarious moieties are defined as above.

The compounds of formula I can be administered as racemic mixtures orenantiomerically pure compounds.

In an embodiment of the compounds of formula I, X is CH.

In another embodiment, Z is N.

In another embodiment, t is 2 and s is 1.

In another embodiment, R², R⁵ and R⁷ are hydrogen.

In another embodiment, R⁴ and R⁷ are alkyl,

In an additional embodiment, R⁴ and R⁷ are methyl.

In an additional embodiment, R¹ is H, —S(O₂)alkyl, —S(O₂)aryl or—S(O₂)cycloalkyl.

In a still additional embodiment, R¹ is H,

In a still additional embodiment, R³ is aryl or aralkyl,

In a still another additional embodiment, R³ is benzyl or phenyl and R⁸is heteroaryl.

In yet an additional preferred embodiment R⁸ is

wherein each R¹⁰ and Y is as defined.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms.

The “heteroaryl” can be optionally substituted by one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. The prefix aza, oxa or thia before the heteroaryl rootname means that at least a nitrogen, oxygen or sulfur atom respectively,is present as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl,isothiazolyl, oxazolyl, thiazolyl pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl,quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and thelike. The term “heteroaryl” also refers to partially saturatedheteroaryl moieties such as, for example, tetrahydroisoquinolyl,tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like, as well aspartially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single is moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group, Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “isolated” or “in isolated form” for a compound refers to thephysical state of said compound after being isolated from a syntheticprocess or natural source or combination thereof. The term “purified” or“in purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula II its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the CDK(s) and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with is inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et at, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts to suchas sodium, lithium, and potassium salts, alkaline earth metal salts suchas calcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of Formula I, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention, as are positional isomers (such as, forexample, 4-pyridyl and 3-pyridyl). Individual stereoisomers of thecompounds of the invention may, for example, be substantially free ofother isomers, or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention can have the S or R configuration as defined by theIUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”“prodrug” and the like, is intended to equally apply to the salt,solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers,positional isomers, racemates or to prodrugs of the inventive compounds.

The term “nucleoside and nucleotide reverse transcriptase inhibitors”(“NRTI” s) as used herein means nucleosides and nucleotides andanalogues thereof that inhibit the activity of HIV-1 reversetranscriptase, the enzyme which catalyzes the conversion of viralgenomic HIV-1 RNA into proviral HIV-1 DNA.

Typical suitable NRTIs include zidovudine (AZT) available under theRETROVIR trade name from Glaxo-Wellcome Inc., Research Triangle, N.C.27709; didanosine (ddl) available under the VIDEX trade name fromBristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC)available under the HIVID trade name from Roche Pharmaceuticals, Nutley,N.J. 07110; stavudine (d4T) available under the ZERIT trademark fromBristol-Myers Squibb Co., Princeton, N.J. 08543; lamivudine (3TC)available under the EPIVIR trade name from Glaxo-Wellcome ResearchTriangle, N.C. 27709; abacavir (1592U89) disclosed in WO96/30025 andavailable under the ZIAGEN trademark from Glaxo-Wellcome ResearchTriangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available underthe PREVON trade name from Gilead Sciences, Foster City, Calif. 94404;lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitordisclosed in EP-0358154 and EP-0736533 and under development byBristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reversetranscriptase inhibitor (in the form of a racemic mixture of BCH-10618and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V,4A7, Canada; emitricitabine [(−)-FTC] licensed from Emory Universityunder Emory Univ. U.S. Pat. No. 5,814,639 and under development byTriangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also calledbeta-L-D4C and named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene) licensedby Yale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD,the purine nucleoside, (−)-beta-D-2,6,-diamino-purine dioxolanedisclosed in EP 0656778 and licensed by Emory University and theUniversity of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707;and lodenosine (FddA),9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stablepurine-based reverse transcriptase inhibitor discovered by the NIH andunder development by U.S. Bioscience Inc., West Conshohocken, Pa. 19428.

The term “non-nucleoside reverse transcriptase inhibitors” (“NNRTI”s) asused herein means non-nucleosides that inhibit the activity of HIV-1reverse transcriptase.

Typical suitable NNRTIs include nevirapine (BI-RG-587) available underthe VIRAMUNE trade name from Boehringer Ingelheim, the manufacturer forRoxane Laboratories, Columbus, Ohio 43216; delaviradine (BHAP, U-90152)available under the RESCRIPTOR trade name from Pharmacia & Upjohn Co.,Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosedin WO94/03440 and available under the SUSTIVA trade name from DupontPharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, afuropyridine-thio-pyrimide under development by Pharmacia and Upjohn,Bridgewater N.J. 08807; AG-1549 (formerly Shionogi # S-1153);5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbonate disclosed in WO 96/10019 and under clinical development byAgouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)discovered by Mitsubishi Chemical Co. and under development by TrianglePharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451)and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697,licensed to Med Chem. Research, which is co-developing (+) calanolide Awith Vita-invest as an orally administrable product.

The term “protease inhibitor” (“9PI”) as used herein means inhibitors ofthe HIV-1 protease, an enzyme required for the proteolytic cleavage ofviral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins),into the individual functional proteins found in infectious HIV-1. HIVprotease inhibitors include compounds having a peptidomimetic structure,high molecular weight (7600 daltons) and substantial peptide character,e.g. CRIXIVAN (available from Merck) as well as nonpeptide proteaseinhibitors e.g., VIRACEPT (available from Agouron).

Typical suitable P is include saquinavir (Ro 31-8959) available in hardgel capsules under the INVIRASE trade name and as soft gel capsulesunder the FORTOVASE trade name from Roche Pharmaceuticals, Nutley, N.J.07110-1199; ritonavir (ABT-538) available under the NORVIR trade namefrom Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639)available under the CRIXIVAN trade name from Merck & Co., Inc., WestPoint, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPTtrade name from Agouron Pharmaceuticals, Inc., LaJolla Calif.92037-1020; amprenavir (141W94), trade name AGENERASE, a non-peptideprotease inhibitor under development by Vertex Pharmaceuticals, Inc.,Cambridge, Mass. 02139-4211 and available from Glaxo-Wellcome, ResearchTriangle, N.C. under an expanded access program; lasinavir (BMS-234475)available from Bristol-Myers Squibb, Princeton, N.J. 08543 (originallydiscovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, acyclic urea discovered by Dupont and under development by TrianglePharmaceuticals; BMS-2322623, an azapeptide under development byBristol-Myers Squibb, Princeton, N.J. 08543, as a 2nd-generation HIV-1PI; ABT-378 under development by Abbott, Abbott Park, Ill. 60064; andAG-1549 an orally active imidazole carbamate discovered by Shionogi(Shionogi #S-1153) and under development by Agouron Pharmaceuticals,Inc., LaJolla Calif. 92037-1020. Other antiviral agents includehydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. Hydroxyurea (Droxia), a ribonucleoside triphosphate reductaseinhibitor, the enzyme involved in the activation of T-cells, wasdiscovered at the NCl and is under development by Bristol-Myers Squibb,in preclinical studies, it was shown to have a synergistic effect on theactivity of didanosine and has been studied with stavudine. IL-2 isdisclosed in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron U.S.Pat. Nos. RE 33653, 4530787, 4569790, 4604377, 4748234, 4752585, and4949314, and is available under the PROLEUKIN (aldesleukin) trade namefrom Chiron Corp., Emeryville, Calif. 94608-2997 as a lyophilized powderfor IV infusion or sc administration upon reconstitution and dilutionwith water; a dose of about 1 to about 20 million IU/day, sc ispreferred; a dose of about 15 million IU/day, sc is more to preferred.IL-12 is disclosed in WO96/25171 and is available from RochePharmaceuticals, Nutley, N.J. 07110-1199 and American Home Products,Madison, N.J. 07940; a dose of about 0.5 microgram/kg/day to about 10microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-aminoacid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933 licensedfrom Duke University to Trimeris which is developing pentafuside incollaboration with Duke University; pentafuside acts by inhibitingfusion of HIV-1 to target membranes. Pentafuside (3-100 mg/day) is givenas a continuous sc infusion or injection together with efavirenz and 2PI's to HIV-1 positive patients refractory to a triple combinationtherapy; use of 100 mg/day is preferred. Yissum Project No. 11607, asynthetic protein based on the HIV-1 Vif protein, is under preclinicaldevelopment by Yissum Research Development Co., Jerusalem 91042, Israel.Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, isavailable from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; itsmanufacture and formulation are described in U.S. Pat. No. 4,211,771.

The term “anti-HIV-1 therapy” as used herein means any anti-HIV-1 drugfound useful for treating HIV-1 infections in man alone, or as part ofmultidrug combination therapies, especially the HAART triple andquadruple combination therapies. Typical suitable known anti-HIV-1therapies include, but are not limited to multidrug combinationtherapies such as (i) at least three anti-HIV-1 drugs selected from twoNRTIs, one PI, a second PI, and one NNRTI; and (ii) at least twoanti-HIV-1 drugs selected from NNRTIs and PIs. Typical suitableHAART—multidrug combination therapies include:

(a) triple combination therapies such as two NRTIs and one PI; or (b)two NRTIs and one NNRTI; and (c) quadruple combination therapies such astwo NRTIs, one PI and a second PI or one NNRTI. In treatment of naivepatients, it is preferred to start anti-HIV-1 treatment with the triplecombination therapy; the use of two NRTIs and one PI is preferred unlessthere is intolerance to P is. Drug compliance is essential. The CD4⁺ andHIV-1-RNA plasma levels should be monitored every 3-6 months. Should toviral load plateau, a fourth drug, e.g., one PI or one NNRTI could beadded.

See the table below wherein typical therapies are further described:ANTI-HIV-1 MULTI DRUG COMBINATION THERAPIES A. Triple CombinationTherapies 1. Two NRTIs¹ + one PI² 2. Two NRTIs¹ + one NNRTI³ B.Quadruple Combination Therapies⁴ Two NRTIs + one PI + a second PI or oneNNRTI C. ALTERNATIVES:⁵ Two NRTI¹ One NRTI⁵ + one PI² Two PIs⁶ + oneNRTI⁷ or NNRTI³ One PI² + one NRTI⁷ + one NNRTI³FOOTNOTES TO TABLE¹One of the following: zidovudine + lamivudine; zidovudine + didanosine;stavudine + lamivudine; stavudine + didanosine; zidovudine + zalcitabine²Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.³Nevirapine or delavirdine.⁴See A-M. Vandamne et al Antiviral Chemistry & Chemotherapy 9:187 at p.193-197 and FIGS. 1 + 2.⁵Alternative regimens are for patients unable to take a recommendedregimen because of compliance problems or toxicity, and for those whofail or relapse on a recommended regimen. Double nucleoside combinationsmay lead to HIV-resistance and clinical failure in many patients.⁶Most data obtained with saquinavir and ritonavir (each 400 mg bid).⁷Zidovudine, stavudine or didanosine.

Specific examples of compounds of the present invention include, but arenot limited to, compounds of formula I, wherein n is 0, t is 2, s is 1,R², R⁵ and R⁷ are hydrogen, R⁴ and R⁶ are methyl,R⁸ is

X is CH, Z is N and R¹ and R³ are as defined in Table 1: TABLE 1 ExampleR¹ R³ A

B PMB

C

D H

E

F

G

Illustrative compounds from Table I above are shown below in Table 1A:TABLE 1A

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can to beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, c cachets and capsules can be used as solid dosageforms suitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.An example of this includes, but is not limited to, water orwater-propylene glycol solutions for parenteral injection or addition ofsweeteners and opacifiers for oral solutions, suspensions and emulsions.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compound of the invention may also be deliverable transdermally. Thetransdermal compositions can take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be deliverable subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining a therapeutically effective amount of the compound havingformula I.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 10 mg to about 500 mg, preferably fromabout 25 mg to about 300 mg, more preferably from about 50 mg to about250 mg, and most preferably from about 55 mg to about 200 mg, accordingto the particular application.

The actual dosage of the inventive compound employed may be varieddepending upon the requirements of the patient and the severity of tothe condition being treated. Determination of the proper dosage regimenfor a particular situation is within the skill of the art. Forconvenience, the total daily dosage may be divided and administered inportions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 100mg/day to about 300 mg/day, preferably 150 mg/day to 250 mg/day, morepreferably about 200 mg/day, in two to four divided doses.

The doses and dosage regimens of the NRTIs, NNRTIs, PIs and other agentsused in combination with the compounds of this invention will bedetermined by the attending clinician in view of the approved doses anddosage regimens in the package inserts or as set forth in the protocols,taking into consideration the age, sex and condition of the patient andthe severity of the condition treated.

In a preferred embodiment, the compound of the present invention can beused to treat Human Immunodeficiency Virus by administering to a patientin need of such treatment a therapeutically effective amount of one ormore compounds having formula I, preferably in combination with one ormore pharmaceutically acceptable carriers. One or more, preferably oneto four, antiviral agents useful in anti-HIV-1 therapy can be used incombination with the compound of the present invention. The antiviralagent or agents can be combined with one or more compounds of thepresent invention in a single dosage form, or the one or more compoundsof the present invention and the antiviral agent or agents may beadministered simultaneously or sequentially as separate dosage forms.

The antiviral agents contemplated for use in combination with thecompound of the present invention comprise nucleoside and nucleotidereverse transcriptase inhibitors, non-nucleoside reverse transcriptaseinhibitors, protease inhibitors and other antiviral drugs listed belownot to falling within these classifications. Specific examples ofantiviral agents include, but are not limited to, zidovudine,lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovirdipivoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4, DAPD,lodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549,MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir,nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir,hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 11607 andAG-1549. In particular, the combinations known as HAART are contemplatedfor use in combination with the compound of this invention.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents maybe administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

Another aspect of the invention provides a method of treating solidorgan transplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis comprising administering to apatient in need of such treatment a therapeutically effective amount ofone or more compounds of formula I, preferably in combination with oneor more pharmaceutically acceptable carriers. In another embodiment, themethod for treating solid organ transplant rejection, graft v. hostdisease, rheumatoid arthritis, inflammatory bowel disease or multiplesclerosis further comprises administering one or more other agentsuseful in the treatment of said diseases in combination with one or morecompounds of formula I.

Agents known in the treatment of rheumatoid arthritis, transplant andgraft v. host disease, inflammatory bowel disease and multiple sclerosiswhich can be administered in combination with the compound of thepresent invention are as follows:

solid organ transplant rejection and graft v. host disease: immunesuppressants such as cyclosporine and Interleukin-10 (IL-10),tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;

inflammatory bowel disease: IL-10 (see U.S. Pat. No. 5,368,854),steroids and azulfidine;

rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide,steroids and mycophenolate mofetil;

multiple sclerosis: interferon-beta, interferon-alpha, and steroids.

Another aspect of the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical composition for use incombination to treat Human Immunodeficiency Virus. In one container, apharmaceutical composition comprises one or more compounds of formula Iin one or more pharmaceutically acceptable carriers, and in separatecontainers, one or more pharmaceutical compositions comprising aneffective amount of one or more antiviral agents or other agents usefulin the treatment of Human Immunodeficiency Virus in one or morepharmaceutically acceptable carriers.

The goal of the HIV-1 therapy of the present invention is to reduce theHIV-1-RNA viral load below the detectable limit. The “detectable limitof HIV-1-RNA” in the context of the present invention means that thereare fewer than about 200 to fewer than about 50 copies of HIV-1-RNA perml of plasma of the patient as measured by quantitative, multi-cyclereverse transcriptase PCR methodology. HIV-1-RNA is preferably measuredin the present invention by the methodology of Amplicor-1 Monitor 1.5(available from Roche Diagnostics) or of Nuclisens HIV-1 QT-1.

The syntheses of the compounds useful in this invention are exemplifiedby the following preparative examples, which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures within the scope of the invention may be apparentto those skilled in the art.

The following terms may be referred to by their abbreviations inparenthesis:

para-methoxybenzyl (PMB);

dichloroethane (EDCL);

p-toluenesulfonic acid (PTSA);

Thin layer chromatography (TLC);

ethyl acetate (AcOEt or EtOAc);

sodium triacetoxyborohydride (NaBH(OAc₃));

di-t-butyl carbonate (BOC₂O);

N,N′-diisopropylethylamine (iPr₂NEt);

triethylamine (Et₃N or TEA);

butoxycarbonyl (n-Boc or Boc);

tetrahydrofuran (THF);

nuclear magnetic resonance spectroscopy (H NMR);

liquid chromatography mass spectrometry (LCMS);

high resolution mass spectrometry (HRMS);

hexane (hex);

milliliters (mL);

millimoles (mmol);

microliters (μl);

grams (g);

milligrams (mg);

room temperature (ambient) about 25° C. (rt).

To a solution of amine 1 (9.50 g, 47.4 mmol) in CH₂Cl₂ (150 mL) wasadded benzaldehyde (6.04 g, 56.9 mmol) and sodium triacetoxyborohydride(12.1 g, 56.9 mmol). The mixture was then stirred at room temperaturefor 16 h. The mixture was diluted with CH₂Cl₂, 1 N NaOH (aq.) was added,and the resultant mixture was stirred at room temperature for 30 min.The aqueous layer was then extracted with CH₂Cl₂ (3×). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated toafford 13.8 g 2 as a yellow oil.

Step 2

To a solution of 2 (13.8 g) in MeOH (120 mL) was added 4 N HCl (indioxane) (40 mL). The solution was stirred at room temperature for 4 h.The solution was concentrated and the crude product was partitionedbetween 1 N HCl and Et₂O. The aqueous layer was extracted with Et₂O (2×)and the organic layers were discarded. The aqueous layer was adjusted topH 10 with 3 N NaOH. The aqueous layer was then extracted with CH₂Cl₂(4×). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated to afford 8.75 g 3 as a clear liquid (96% yield).

Step 3

To a solution of the amine 3 (8.75 g, 46 mmol) in toluene (100 mL) wasadded Boc-piperidone 4 (9.2 g, 46 mmol) and p-toluenesulfonic acid (44mg, 0.23 mmol). The solution was heated to reflux with a Dean-Stark trapattached. The solution was stirred at reflux for 6 h. The solution wasconcentrated to approx. ½ the original volume. Acetone cyanohydrin (4.5g, 52.9 mmol) was added and the solution was heated to reflux for 1 h.The solution was then cooled to 0° C. To the solution was added THF (125mL) followed by the slow addition of methyl magnesium bromide (3Msolution in Et₂O) (77 mL, 230 mmol). The resultant solution was stirredat 0° C. for 1 h, then continued to stir at room temperature for anadditional 16 h. The mixture was poured into a mixture of ice and 25%sodium citrate solution and stirred at room temperature for 30 min. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.The crude product was purified by flash chromatography (2:1hexanes:EtOAc) for afford 6 (15.1 g) as a clear oil (85% yield).

Step 4

To a nitrogen degassed solution of amine 6 (6.8 g, 17.5 mmol) in MeOH(100 mL) in a pressure vessel was added palladium hydroxide on carbon(20% Pd by wt.) (1.22 g. 0.90 mmol). The vessel was sealed, purged withnitrogen, and pressurized to 60 psi with hydrogen and stirred at roomtemperature for 3.5 days. The solution was purged with nitrogen,filtered through Celite, and concentrated to afford 7 (5-2 g) as an offwhite solid (100% yield).

Step 5

To a solution of the amino alcohol 8 (10 g, 87 mmol) in CH₂Cl₂ (300 mL)was added p-anisaldehyde (14.2 g, 104 mmol) and sodiumtriacetoxyborohydride (22 g, 104 mmol) and stirred the mixture at roomto temperature for 16 h. The mixture was diluted with CH₂Cl₂. Theorganic layer was washed with 1 N NaOH (2×). The organic layer was thendried over Na₂SO₄, filtered, and concentrated. The crude product waspartitioned between 3 N HCl and Et₂O. The aqueous layer was extractedwith Et₂O (2×) and the organic layers were discarded. The aqueous layerwas adjusted to pH 10 with 3 N NaOH. The aqueous layer was thenextracted with EtOAc (4×). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated to afford 9 (18.5g),

Step 6

To a solution of DMSO (7.98 g, 102 mmol) in CH₂Cl₂ (200 mL) at −78° C.was added oxalyl chloride (13.0 g, 102 mmol). The resultant solution wasstirred at −78° C. for 30 min. The alcohol 9 (18.5 g, 78.7 mmol) inCH₂Cl₂ (50 mL) was then added to the solution of the oxidant. Theresultant solution was stirred at −78° C. for 1 h. Triethyl amine (23.8g, 236 mmol) was added to the solution and the resultant solution wasstirred at −78° C. for 30 min. followed by stirring at room temperaturefor an additional 1 h. The solution was poured into 1 N NaOH andextracted with CH₂Cl₂ (3×). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to afford 10 (18 g) as a yellow oil.

Step 7

To a solution of aldehyde 9 (3.07 g, 13.2 mmol) in benzene (100 mL) wasadded amine 7 (3.91 g, 13.2 mmol) followed by benzotriazole 11 (1.57 g,13.2 mmol). The solution was heated to reflux with a Dean-Stark trapattached for 7 h. The solution was concentrated to provide 12 (8.3 g) asa brown foam.

Step 8

To a solution of 12 (3.93 g, 6.2 mmol) in THF (100 mL) was added phenylmagnesium chloride (25 mmol). The solution was stirred at roomtemperature for 6 h. The solution was poured into a 25% sodium citratesolution and extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by prep TLC to afford diastereomer #1 700 mg(higher Rf by TLC) and 800 mg diastereomer #2 (lower Rt by TLC).

Step 9

To a solution of 13 diastereomer #1 (175 mg, 0.30 mmol) in MeOH (10 mL)was added 4M HCl (in dioxane). Stirred at room temperature for 3 h. Thesolution was concentrated and the crude product was partitioned betweenCH₂Cl₂ and NaHCO₃. The aqueous layer was extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The amine was dissolved in MeCN (2 mL). The pyrimidineacid (69 mg, 0.45 mmol), EDCl (87 mg, 0.45 mmol), HOBt (61 mg, 0.045mmol), and iPr₂NEt (194 mg, 1.50 mmol) were added. The solution wasstirred at room temperature for 2 days. The solution was thenconcentrated. The crude product was partitioned between EtOAc and 1 MNaOH. The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by prep TLC (97:3EtOAc:Et₃N) to afford 50 mg (27% yield) as a yellow oil.

Step 10

To a solution of the PMB amine 14 (50 mg, 0.08 mmol) in CH₂Cl₂ (2 mL) at0° C. was added 1-chloroethyl chloroformate (15 mg, 0.10 mmol). Thesolution was stirred at 0° C. for 1 h. The solution was concentrated andthe product was redissolved in MeOH (10 mL). The solution was heated toreflux for 45 min. The solution was then concentrated. The crude productwas partitioned between CH₂Cl₂ and NaHCO₃. The aqueous layer wasextracted with CH₂Cl₂ (3×). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to afford the amine 15 (41 mg) as ayellow oil.

Step 11

To a solution of the amine 15 (40 mg) in CH₂Cl₂ (1 mL) was added Et₃N(12 mg, 0.12 mmol) and cyclopropyl sulfonyl chloride (13 mg, 0.10 mmol).The solution was stirred at room temperature for 16 h. Diluted withCH₂Cl₂. Added NaHCO₃ (aq.). The aqueous layer was extracted with CH₂CO₂(3×). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by prep TLC (5%MeOH/CH₂Cl₂) to afford the sulfonamide 16 (15 mg 31% yield) as a yellowoil.

The other compounds of the invention (e.g., those listed in Table 1 andTable 1A) could also be prepared by similar methods, using the variouslyapplicable starting materials.

The following assays can be used to determine the CCR5 inhibitory andantagonistic activity of the compounds of the invention.

CCR5 Membrane Binding Assay:

A high throughput screen utilizing a CCR5 membrane binding assayidentifies inhibitors of RANTES binding. This assay utilizes membranesprepared from NIH 3T3 cells expressing the human CCR5 chemokine receptorwhich have the ability to bind to RANTES, a natural ligand for thereceptor. Using a 96-well plate format, membrane preparations areincubated with ¹²⁵I-RANTES in the presence or absence of compound forone hour. Compounds are serially diluted over a wide range of 0.001μg/ml to 1 μg/ml and tested in triplicates, Reaction cocktails areharvested through glass fiber filters, and washed thoroughly. Totalcounts for replicates are averaged and data reported as theconcentration required to inhibit 50 percent of total ¹²⁵I-RANTESbinding. Compounds with potent activity in the membrane binding assayare further characterized in secondary cell-based HIV-1 entry andreplication assays.

HIV-1 Entry Assay:

Replication defective HIV-1 reporter virions are generated bycotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (whichhas been modified by mutation of the envelope gene and introduction of aluciferase reporter plasmid) along with a plasmid encoding one ofseveral HIV-1 envelope genes as described by Connor et al, Virology, 206(1995), p. 935-944. Following transfection of the two plasmids bycalcium phosphate precipitation, the viral supernatants are harvested onday 3 and a functional viral titer determined. These stocks are thenused to infect U87 cells stably expressing CD4 and the chemokinereceptor CCR5 which have been preincubated with or without testcompound. Infections are carried out for 2 hours at 37° C., the cellswashed and media replaced with fresh media containing compound. Thecells are incubated for 3 days, lysed and luciferase activitydetermined. Results are reported as the concentration of compoundrequired to inhibit 50% of the luciferase activity in the controlcultures.

HIV-1 Replication Assay:

This assay uses primary peripheral blood mononuclear cells or the stableU87-CCR5 cell line to determine the effect of anti-CCR5 compounds toblock infection of primary HIV-1 strains. The primary lymphocytes arepurified from normal healthy donors and stimulated in vitro with PHA andIL-2 three days prior to infection. Using a 96-well plate format, cellsare pretreated with drug for 1 hour at 37° C. and subsequently infectedwith an M-tropic HIV-1 isolates. Following infection, the cells arewashed to remove residual inoculum and cultured in the presence ofcompound for 4 days. Culture supernatants are harvested and viralreplication measured by determination of viral p24 antigenconcentration.

Calcium Flux Assay:

Cells expressing the HIV coreceptor CCR5 are loaded with calciumsensitive dyes prior to addition of compound or the natural CCR5 ligand.Compounds with agonist properties will induce a calcium flux signal inthe cell, while the compounds of this invention are identified ascompounds which do not induce signaling by themselves but are capable ofblocking signaling by the natural ligand RANTES.

GTPγS Binding Assay (Secondary Membrane Binding Assay):

A GTPγS binding assay measures receptor activation by CCR5 ligands. Thisassay measures the binding of ³⁵S labeled-GTP to receptor coupledG-proteins that occurs as a result of receptor activation by anappropriate ligand. In this assay, the CCR5 ligand, RANTES, is incubatedwith membranes from CCR5 expressing cells and binding to the receptoractivation (or binding) is determined by assaying for bound ³⁵S label.The assay quantitatively determines if compounds exhibit agonistcharacteristics by inducing activation of the receptor or alternativelyantagonist properties by measuring inhibition of RANTES binding in acompetitive or non-competitive fashion.

Chemotaxis Assay:

The chemotaxis assay is a functional assay which characterizes theagonist vs. antagonist properties of the test compounds. The assaymeasures the ability of a non-adherent murine cell line expressing humanCCR5 (BaF-550) to migrate across a membrane in response to either testcompounds or natural ligands (i.e., RANTES, MIP-1β). Cells migrateacross the permeable membrane towards compounds with agonist activity.Compounds that are antagonists not only fail to induce chemotaxis, butare also capable of inhibiting cell migration in response to known CCR5ligands.

Luciferase Replication Assay:

Plasmids encoding the full length genome of HIV-1 pNL-4-Luc with the gp120 V-3 loop replaced by the Bgl II fragment of HIV-1 ADA, YU-2 or HxB(ADA-Luc-FL, YU-2-Luc-FL and HxB-Luc-FL) are obtained from Dr. SusanPontow (Washington University, St. Louis Mo.). Replication-competentluciferase reporter virus stocks are generated by transfection ofplasmids into 293T cells using Superfect (Qiagen) or Mirus transfectionreagents. Viral stocks are collected 48 hours following transfection andtitered for luciferase production on U-87-CCR5 or CXCR4 cells,U87-CD4-CCR5 cells (10⁴/well) are plated in 96-well cell culture platesand incubated overnight. Media is removed and replaced with 50 μl offresh culture media (DMEM, 10% FCS) and 50 μl of compound diluted inculture medium. Cells are incubated with compound at 37° C. for 1 hour.The resultant supernatant is removed and replaced with 20 μl of mediacontaining compound and infected with an equal volume of diluted orundiluted virus stock at 37° C. for 3-4 hours. The cells are washed oncewith DMEM, and 200 μl of media containing compound is added. Thecultures are incubated for 3 days, the cells lysed in luciferase lysisbuffer (Promega, Madison, Wis.) and transferred to Immulon plates (DynexTechnologies, Chantilly Va.). An equal volume of luciferase substrate(Promega, Madison Wis.) is added to lysates and the plates readimmediately in a Wallac Luminometer. Fifty and ninety percent inhibitoryconcentrations are determined using GraphPad PRISM software. HIVReplication HRMS Example Structure (Luciferase) IC₅₀ nM Found (MH⁺) 1

2 623.3750 1:1 mixture of diastereomers 2

25 639.4394 1:1 mixture of diastereomers 3

2 693.3362 1:1 mixture of diastereomers 4

4 519.3813 1:1 mixture of diastereomers 5

15 631.3437 Diastereomer #1 6

0.7 631.3437 Diastereomer #2 7

0.5 605.3278 Diastereomer #1 8

1.6 625.4240 1/1 mix of diastereomers 9

11 505.3655 1/1 mix of diastereomers 10

3 641.3655 11

0.3 613.3333 1/1 mix of diastereomers 12

1 599.3207 13

0.7 635.3191 14

2 573.3026 15

5 563.3515 16

4 595.3416 17

0.4 631.6452 18

17 569.3261 19

13 559.3769

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A pharmaceutical composition comprising: (a) a therapeuticallyeffective amount of one or more compounds of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: n is0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4 t is 1, 2, 3 or 4 with theprovisos that i) when n is 0 and s is 2, then t is 1, 3 or 4; and ii)when n is 0 and t is 2, then s is 0, 1, 3 or 4; X is N; Z is N or CH; R¹is H, alkyl, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²¹; R², R⁴,R⁵, R⁶ and R⁷ can be the same or different each being independently H oralkyl; R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl orheteroaryl; or R² and R³ taken together are ═N(O-alkyl), ═N(OH),═N—N(R²⁰R²¹) or ═CH(alkyl) provided that when one or both of X and Z isN, R² and R³ together are not ═CH(alkyl); R⁸ is aryl, heteroaryl,fluorenyl; and diphenylmethyl, heteroaryl-N-oxide,

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is unsubstituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R¹³, R¹⁴ and R¹⁵; R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH,—OCH₃, —NH₂, —N(H)C(O)N(H)alkyl, —NHS(O₂)R²⁰ or —N(H)C(O)alkyl; R¹¹ andR¹² can be the same or different and are each independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, —NR¹⁸R¹⁹, —OH,—CF₃, —OCH₃, —O-acyl and —OCF₃; R¹³ is selected from the groupconsisting of H, R¹¹, aryl, —NO₂, —CN, —CH₂F, —CHF₂, —C(O)H, —CH═NOR¹⁸,pyridyl-N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰,—N(H)C(O)N(H)(haloalkyl), —N(H)C(O)N(H)(cycloalkylalkyl),—N(H)C(O)alkyl, —N(H)C(O)CF₃, —N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl,—N(S(O₂)CF₃)₂, —N(H)C(O)Oalkyl, cycloalkyl, —SR²¹, —S(O)R²¹, —S(O₂)R²¹,—S(O₂)N(H)(alkyl), —OS(O₂)alkyl, —OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹,—C(O)N(CH₂CH₂—O—CH₃)₂, —OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and—B(OC(CH₃)₂)₂; R¹⁴ is selected from the group consisting of alkyl,haloalkyl, NH₂ and R¹⁵-phenyl; R¹⁵ is 1 to 3 substituents selected fromthe group consisting of H, alkyl, haloalkyl, —CF₃, —CO₂R¹⁹, —CN, alkoxyand halogen; wherein said R¹⁵ moieties can be the same or different eachbeing independently selected when there are more than one R¹⁵ present;R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms; R¹⁸, R¹⁹ and R²⁰ caneach be the same or different and are each independently selected fromthe group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl; andR²¹ is selected from the group consisting of alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl; wherein each ofsaid alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy, hydroxyalkyl,heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkyl in thedefinitions above can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, where said moieties are independently selected from the groupconsisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹, —C(O)NR¹⁸R¹⁹,—N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)OR¹⁸, —OCF₃, —CF₃,—S(O₂)R¹⁸ and —C(O)R¹⁸; and (b) one or more antiviral or other agentsuseful in the treatment of Human Immunodeficiency Virus.
 2. Thepharmaceutical composition of claim 1, wherein in structural formula I,R¹ and R³ are as defined in the following table: R¹ R³

PMB

H


3. The pharmaceutical composition of claim 1, wherein the compound ofstructural Formula I is a compound represented by the structuralformulae:

or a pharmaceutically acceptable salt or solvate thereof.
 4. Thepharmaceutical composition of claim 1, wherein said antiviral agent isselected from the group consisting of nucleoside reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors and proteaseinhibitors.
 5. The pharmaceutical composition of claim 1, wherein saidantiviral agent is selected from the group consisting of zidovudine,lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovirdipivoxil, lobucavir. BCH-10652, emitricitabine, beta-L-FD4, DAPD,lodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549,MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir,nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir,hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 11607 andAG-1549.
 6. A method of treating Human Immunodeficiency Virus comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of one or more compounds of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: n is0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4; t is 1, 2, 3 or 4 with theprovisos that i) when n is 0 and s is 2, then t is 1, 3 or 4; and ii)when n is 0 and t is 2, then s is 0, 1, 3 or 4; X is N; Z is N or CH; R¹is H, alkyl, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²¹; R², R⁴,R⁵, R⁶ and R⁷ can be the same or different each being independently H oralkyl; R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl orheteroaryl; or R² and R³ taken together are ═N(O-alkyl), ═N(OH),═N—N(R²⁰R²¹) or ═CH(alkyl) provided that when one or both of X and Z isN, R² and R³ together are not ═CH(alkyl); R⁸ is aryl, heteroaryl,fluorenyl; and diphenylmethyl, heteroaryl-N-oxide,

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is unsubstituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R³, R¹⁴ and R¹⁵; R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH,—OCH₃, —NH₂, —N(H)C(O)N(H)alkyl, —NHS(O₂)R²⁰ or —N(H)C(O)alkyl; R¹¹ andR¹² can be the same or different and are each independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, —NR¹⁸R¹⁹, —OH,—CF₃, —OCH₃, —O-acyl and —OCF₃; R¹³ is selected from the groupconsisting of H, R¹¹, aryl, —NO₂, —CN, —CH₂F, —CHF₂₁—C(O)H, CH═NOR¹⁸,pyridyl-N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰,—N(H)C(O)N(H)(haloalkyl), —N(H)C(O)N(H)(cycloalkylalkyl),—N(H)C(O)alkyl, —N(H)C(O)CF₃, —N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl,—N(S(O₂)CF₃)₂, —N(H)C(O)Oalkyl, cycloalkyl, —SR²¹—S(O)R²¹, —S(O₂)R²¹,—S(O₂)N(H)(alkyl), —OS(O₂)alkyl, —OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹,—C(O)N(CH₂CH₂—O—CH₃)₂, —OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and—B(OC(CH₃)₂)₂; R¹⁴ is selected from the group consisting of alkyl,haloalkyl, NH₂ and R¹⁵-phenyl; R¹⁵ is 1 to 3 substituents selected fromthe group consisting of H, alkyl, haloalkyl, —CF₃, —CO₂R¹⁹, —CN, alkoxyand halogen; wherein said R¹⁵ moieties can be the same or different eachbeing independently selected when there are more than one R¹⁵ present;R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms; R¹⁸, R¹⁹ and R²⁰ caneach be the same or different and are each independently selected fromthe group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl; andR²¹ is selected from the group consisting of alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl; wherein each ofsaid alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy, hydroxyalkyl,heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkyl in thedefinitions above can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, where said moieties are independently selected from the groupconsisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹, —C(O)NR¹⁸R¹⁹,—N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)R¹⁸, —OCF₃, —CF₃,—S(O₂)R¹⁸ and —C(O)R¹⁸.
 7. The method of claim 6, wherein in structuralformula I, R¹ and R³ are as defined in the following table: R¹ R³

PMB

H


8. The method of claim 6, wherein the compound of structural Formula Iis a compound represented by the structural formulae:

or a pharmaceutically acceptable salt or solvate thereof.
 9. The methodof claim 6, further comprising administering one or more antiviral orother agents useful in the treatment of Human Immuno-deficiency Virus.10. The method of claim 9, wherein said antiviral agent is selected fromthe group consisting of nucleoside reverse transcriptase inhibitors,non-nucleoside reverse transcriptase inhibitors and protease inhibitors.11. The method of claim 10, wherein said antiviral agent is selectedfrom the group consisting of zidovudine, lamivudine, zalcitabine,didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir,BCH-10652, emitricitabine, beta-L-FD4, DAPD, lodenosine, nevirapine,delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442, (+)-calanolide Aand B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP-450,BMS-2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, IL-2, IL-12,pentafuside, Yissum No. 11607 and AG-1549.
 12. A method of treatingsolid organ transplant rejection, graft v. host disease, arthritis,rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis,psoriasis, asthma, allergies or multiple sclerosis comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of one or more compounds of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: n is0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4; t is 1, 2, 3 or 4 with theprovisos that i) when n is 0 and s is 2, then t is 1, 3 or 4; and ii)when n is 0 and t is 2, then s is 0, 1, 3 or 4; X is N; Z is N or CH; R¹is H, alkyl, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²¹; R², R⁴,R⁵, R⁶ and R⁷ can be the same or different each being independently H oralkyl; R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl orheteroaryl; or R² and R³ taken together are —N(O-alkyl), ═N(OH),═N—N(R²⁰R²¹) or ═CH(alkyl) provided that when one or both of X and Z isN, R² and R³ together are not ═CH(alkyl); R⁸ is aryl, heteroaryl,fluorenyl; and diphenylmethyl, heteroaryl-N-oxide,

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is unsubstituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R¹³, R¹⁴ and R¹⁵; R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH,—OCH₃, —NH₂, —N(H)C(O)N(H)alkyl, —NHS(O₂)R²⁰ or —N(H)C(O)alkyl; R¹¹ andR¹² can be the same or different and are each independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, —NR¹⁸R¹⁹, —OH,—CF₃, —OCH₃, —O-acyl and —OCF₃; R¹³ is selected from the groupconsisting of H, R¹¹, aryl, —NO₂, —CN, —CH₂F, —CHF₂, —C(O)H, —CH═NOR¹⁸,pyridyl-N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰,—N(H)C(O)N(H)(haloalkyl), —N(H)C(O)N(H)(cycloalkylalkyl),—N(H)C(O)alkyl, —N(H)C(O)CF₃, —N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl,—N(S(O₂)CF₃)₂, —N(H)CO)Oalkyl, cycloalkyl, —SR²¹, —S(O)R²¹, —S(O₂)R²¹,—S(O₂)N(H)(alkyl), —OS(O₂)alkyl, —OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹,—C(O)N(CH₂CH₂—O—CH₃)₂, —OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and—B(OC(CH₃)₂)₂; R¹⁴ is selected from the group consisting of alkyl,haloalkyl, NH₂ and R¹⁵-phenyl; R¹⁵ is 1 to 3 substituents selected fromthe group consisting of H, alkyl, haloalkyl, —CF₃, —CO₂R¹⁹, —CN, alkoxyand halogen; wherein said R¹⁵ moieties can be the same or different eachbeing independently selected when there are more than one R¹⁵ present;R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms; R¹⁸, R¹⁹ and R²⁰ caneach be the same or different and are each independently selected fromthe group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl; andR²¹ is selected from the group consisting of alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl; wherein each ofsaid alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy, hydroxyalkyl,heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkyl in thedefinitions above can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, where said moieties are independently selected from the groupconsisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹, —C(O)NR¹⁸R¹⁹,—N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)OR¹⁸, OCF₃, —CF₃,—S(O₂)R¹⁸ and —C(O)R¹⁸.
 13. The method of claim 12, wherein instructural formula I, R¹ and R³ are as defined in the following table:R¹ R³

PMB

H


14. The method of claim 12, wherein the compound of structural Formula Iis a compound represented by the structural formulae:

or a pharmaceutically acceptable salt or solvate thereof.
 15. The methodof claim 12, further comprising administering with said one or morecompounds, one or more pharmaceutically acceptable carriers.
 16. Themethod of claim 15, further comprising administering one or moreadditional agents useful in the treatment of said diseases.
 17. A kitcomprising in separate containers in a single package pharmaceuticalcompositions for use in combination to treat Human ImmunodeficiencyVirus which comprises: (a) in one container a pharmaceutical compositioncomprising one or more compounds_of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: n is0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4; t is 1, 2, 3 or 4 with theprovisos that i) when n is 0 and s is 2, then t is 1, 3 or 4; and ii)when n is 0 and t is 2, then s is 0, 1, 3 or 4; X is N; Z is N or CH; R¹is H, alkyl, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²⁴; R², R⁴,R⁵, R⁶ and R⁷ can be the same or different each being independently H oralkyl; R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl orheteroaryl; or R² and R³ taken together are ═N(O-alkyl), —N(OH),═N—N(R²⁰R²¹) or ═CH(alkyl) provided that when one or both of X and Z isN, R² and R³ together are not ═CH(alkyl); R⁸ is aryl, heteroaryl,fluorenyl; and diphenylmethyl, heteroaryl-N-oxide,

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is unsubstituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R¹³, R¹⁴ and R¹⁵; R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH,—OCH₃, —NH₂, —N(H)C(O)N(H)alkyl, —NHS(O₂)R²⁰ or —N(H)C(O)alkyl; R¹¹ andR¹² can be the same or different and are each independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, —NR¹⁸R¹⁹, —OH,—CF₃, —OCH₃, —O-acyl and —OCF₃; R¹³ is selected from the groupconsisting of H, R¹¹, aryl, —NO₂, —CN, —CH₂F, —CHF₂, —C(O)H, —CH═NOR¹⁸,pyridyl-N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰,—N(H)C(O)N(H)(haloalkyl), —N(H)C(O)N(H)(cycloalkylalkyl),—N(H)C(O)alkyl, —N(H)C(O)CF₃, —N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl,—N(S(O₂)CF₃)₂, —N(H)C(O)Oalkyl, cycloalkyl, —SR²¹, —S(O)R²¹, —S(O₂)R²¹,—S(O₂)N(H)(alkyl), —OS(O₂)alkyl, —OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹,—C(O)N(CH₂CH₂—O—CH₃)₂, —OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and—B(OC(CH₃)₂)₂; R¹⁴ is selected from the group consisting of alkyl,haloalkyl, NH₂ and R¹⁵-phenyl; R¹⁵ is 1 to 3 substituents selected fromthe group consisting of H, alkyl, haloalkyl, —CF₃, —CO₂R¹⁹, —CN, alkoxyand halogen; wherein said R¹⁵ moieties can be the same or different eachbeing independently selected when there are more than one R¹⁵ present;R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms; R¹⁸, R¹⁹ and R²⁰ caneach be the same or different and are each independently selected fromthe group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl; andR²¹ is selected from the group consisting of alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl; wherein each ofsaid alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy, hydroxyalkyl,heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkyl in thedefinitions above can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, where said moieties are independently selected from the groupconsisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹, —CO)NR¹⁸R¹⁹,—N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)OR¹⁸, —OCF₃, —CF₃,—S(O₂)R¹⁸ and —C(O)R¹⁸ in one or more pharmaceutically acceptablecarriers; and (b) in a separate container, one or more pharmaceuticalcompositions comprising one or more antiviral or other agents useful inthe treatment of Human Immunodeficiency Virus in one or morepharmaceutically acceptable carriers.
 18. The kit of claim 17, whereinin structural formula I, R¹ and R³ are as defined in the followingtable: R¹ R³

PMB

H


19. The kit of claim 17, wherein the compound of structural Formula I isa compound represented by the structural formulae:

or a pharmaceutically acceptable salt or solvate thereof.
 20. A processfor making a pharmaceutical composition, comprising combining (a) atleast one compound of structural formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: n is0, 1, 2, 3 or 4; s is 0, 1, 2, 3 or 4; t is 1, 2, 3 or 4 with theprovisos that i) when n is 0 and s is 2, then t is 1, 3 or 4; and ii)when n is 0 and t is 2, then s is 0, 1, 3 or 4; X is N; Z is N or CH; R¹is H, alkyl, aralkyl, —S(O₂)alkyl, —S(O₂)aryl, —C(O)alkyl, —C(O)aryl,-alkyl-aryl-R⁸, -alkyl-heteroaryl-R⁸, —S(O₂)cycloalkyl, —S(O₂)-aryl-R⁸,—C(O)cycloalkyl, —C(O)-aryl-R⁸, —C(O)NR²⁰R²¹ or —S(O₂)NR²⁰R²¹; R², R⁴,R⁵, R⁶ and R⁷ can be the same or different each being independently H oralkyl; R³ is H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl orheteroaryl; or R² and R³ taken together are ═N(O-alkyl), ═N(OH),═N—N(R²⁰R²¹) or —CH(alkyl) provided that when one or both of X and Z isN, R² and R³ together are not ═CH(alkyl); R⁸ is aryl, heteroaryl,fluorenyl; and diphenylmethyl, heteroaryl-N-oxide,

wherein each R¹⁰ is the same or different and independently selectedfrom —CH₃ or halogen, Y is N or N(→O) and each of said aryl, fluorenyl,diphenyl and heteroaryl is unsubstituted or optionally independentlysubstituted with 1 to 4 substituents which substituents can be the sameor different each being independently selected from the group consistingof R¹¹, R¹², R¹³, R¹⁴ and R¹⁵; R⁹ is H, alkyl, —CF₃, cycloalkyl, —OH,—OCH₃, —NH₂, —N(H)C(O)N(H)alkyl, —NHS(O₂)R²⁰ or —N(H)C(O)alkyl; R¹¹ andR¹² can be the same or different and are each independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, —NR¹⁸R¹⁹, —OH,—CF₃, —OCH₃, —O-acyl and —OCF₃; R¹³ is selected from the groupconsisting of H, R¹¹, aryl, —NO₂, —CN, —CH₂F, —CHF₂, —C(O)H, —CH═NOR¹⁸,pyridyl-N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁹)CONR¹⁹R²⁰,—N(H)C(O)N(H)(haloalkyl), —N(H)C(O)N(H)(cycloalkylalkyl),—N(H)C(O)alkyl, —N(H)C(O)CF₃, —N(H)S(O₂)N(alkyl)₂, —N(H)S(O₂)alkyl,—N(S(O₂)CF₃)₂, —N(H)C(O)Oalkyl, cycloalkyl, —SR²¹, —S(O)R²¹, —S(O₂)R²¹,—S(O₂)N(H)(alkyl), —OS(O₂)alkyl, —OS(O₂)CF₃, hydroxyalkyl, —C(O)NR¹⁸R¹⁹,—C(O)N(CH₂CH₂—O—CH₃)₂, —OC(O)N(H)alkyl, —CO₂R¹⁸, —Si(CH₃)₃ and—B(OC(CH₃)₂)₂; R¹⁴ is selected from the group consisting of alkyl,haloalkyl, NH₂ and R¹⁵-phenyl; R¹⁵ is 1 to 3 substituents selected fromthe group consisting of H, alkyl, haloalkyl, —CF₃, —CO₂R¹⁹, —CN, alkoxyand halogen; wherein said R¹⁵ moieties can be the same or different eachbeing independently selected when there are more than one R¹⁵ present;R¹⁶ and R¹⁷ can be the same or different each being independentlyselected from the group consisting of hydrogen and alkyl, or R¹⁶ and R¹⁷together are an alkylene group and with the carbon to which they areattached form a spiro ring of 3 to 6 carbon atoms; R¹⁸, R¹⁹ and R²⁰ caneach be the same or different and are each independently selected fromthe group consisting of H, alkyl, cycloalkyl, aryl and heteroaryl; andR²¹ is selected from the group consisting at alkyl, haloalkyl,hydroxyalkyl, alkylene, cycloalkyl, aryl and aralkyl; wherein each ofsaid alkyl, alkylene, aryl, arylalkyl, aralkyl, alkoxy, hydroxyalkyl,heteroaryl, heteroaralkyl, cycloalkylalkyl and cycloalkyl in thedefinitions above can be unsubstituted or optionally independentlysubstituted with one or more moieties which can be the same ordifferent, where said moieties are independently selected from the groupconsisting of —OH, alkoxy, —CN, halogen, —NR¹⁸R¹⁹, —C(O)NR¹⁸R¹⁹,—N(R¹⁸)C(O)R¹⁹, —N(R¹⁸)S(O₂)R¹⁹, —S(O₂)NR¹⁸R¹⁹, —C(O)OR¹⁸, —OCF₃—CF₃,—S(O₂)R¹⁸ and —C(O)R¹⁸; and (b) at least one pharmaceutically acceptablecarrier.